Cholewinski Tomasz, Pereira Diana, Moerland Matthijs, Jacobs Gabriel E
Centre for Human Drug Research, Leiden, The Netherlands.
Centre for Human Drug Research, Zernikedreef 8, 2333 CL Leiden, The Netherlands.
Ther Adv Psychopharmacol. 2021 Oct 28;11:20451253211036814. doi: 10.1177/20451253211036814. eCollection 2021.
Major depressive disorder (MDD) is a multifactorial psychiatric disorder with obscure pathophysiology. A biomarker-based approach in combination with standardized interview-based instruments is needed to identify MDD subtypes and novel therapeutic targets. Recent findings support the impairment of the mammalian target of rapamycin complex 1 (mTORC1) in MDD. No well-established biomarkers of mTORC1 disease- and treatment-modulated activity are currently available for use in early phase antidepressant drug (AD) development. This review aims to summarize biomarkers of mTORC1 activity in MDD and to suggest how these could be implemented in future early clinical trials on mTORC1 modulating ADs. Therefore, a PubMed-based narrative literature review of the mTORC1 involvement in MDD was performed. We have summarized recent pre-clinical and clinical findings linking the MDD to the impaired activity of several key biomarkers related to mTORC1. Also, cases of restoration of these impairments by classical ADs and novel fast-acting investigational ADs are summarized. The presented biomarkers may be used to monitor pharmacological effects by novel rapid-acting mTORC1-targeting ADs. Based on findings in the peripheral blood mononuclear cells, we argue that those may serve as an model for evaluation of mTORC1 activity and propose the use of the summarized biomarkers for this purpose. This could both facilitate the selection of a pharmacodynamically active dose and guide future early clinical efficacy studies in MDD. In conclusion, this review provides a blueprint for the rational development of rapid-acting mTORC1-targeting ADs.
重度抑郁症（MDD）是一种病理生理学尚不明确的多因素精神障碍。需要一种基于生物标志物的方法与标准化的基于访谈的工具相结合，以识别MDD亚型和新的治疗靶点。最近的研究结果支持雷帕霉素复合物1（mTORC1）的哺乳动物靶点在MDD中受损。目前尚无成熟的可用于早期抗抑郁药物（AD）研发的mTORC1疾病和治疗调节活性的生物标志物。本综述旨在总结MDD中mTORC1活性的生物标志物，并提出如何在未来关于mTORC1调节性AD的早期临床试验中应用这些生物标志物。因此，我们基于PubMed对mTORC1参与MDD的相关文献进行了叙述性综述。我们总结了近期将MDD与几种与mTORC1相关的关键生物标志物活性受损联系起来的临床前和临床研究结果。此外，还总结了经典AD和新型速效研究性AD恢复这些损伤的案例。所提出的生物标志物可用于监测新型速效mTORC1靶向AD的药理作用。基于外周血单个核细胞的研究结果，我们认为这些细胞可作为评估mTORC1活性的模型，并建议为此目的使用所总结的生物标志物。这既有助于选择具有药效学活性的剂量，也可为未来MDD的早期临床疗效研究提供指导。总之，本综述为速效mTORC1靶向AD的合理研发提供了蓝图。
